Early childhood caries (ECC) is the most common chronic disease of childhood, and one that is characterized by marked social, economic, and racial disparities. The prevalence of ECC in the US increased by 15% during the last 2 decades, and according to the most recent national data 28% of children ages 2-5 are affected. Importantly, management of ECC among young children often requires complex and costly restorative procedures with the use of advanced behavior management techniques including sedation and general anesthesia. ECC can have severe sequelae for children's general health and well-being, and confers important social and economic impacts on their families, communities, and the health system. Caries is a multifactorial disease with a substantial genetic component, which is estimated between 40-60%, but little is known regarding specific contributing genetic factors. A large-scale genome-wide association study (GWAS) involving a multi-cohort meta-analysis recently nominated 29 loci as associated with dental caries among adult, predominantly European-American (EA), populations. So far, the only GWAS examining caries in the primary dentition employed a sample of 1,300 3-12 year-old EA children and nominated 7 genes, 2 of which showed additional evidence of association in follow-up studies among children and adults. Here, we propose to conduct a large-scale GWAS of ECC involving a multi-ethnic community-based sample of 6,000 children ages 3 and 4. For Aim 1, we will undertake a comprehensive clinical dental characterization of a state-representative sample of approximately 6,000 children enrolled in Early Head Start and Head Start programs in North Carolina. We will use a tested clinical examination protocol including saliva sample collection for DNA extraction, and will use the latest International Caries Diagnosis System (ICDAS) visual diagnostic criteria to determine disease prevalence and severity. We will collect and store dental plaque samples for future microbiome analyses that will be funded separately. To identify genetic variants that are associated with ECC, in Aim 2, we will conduct a trans-ethnic GWAS of ECC and related traits, utilizing high-density genotyping, imputation to 1000 Genomes Project reference panels and advanced statistical approaches to leverage differences in genetic structure between racial/ethnic groups. In Aim 3, we will utilize publicly available GWAS data of early childhood and adult caries, to determine the racial/ethnic and age-group generalization/transferability of loci, genes, and gene sets/pathways identified in our study. Our group's experience in conducting dental epidemiologic studies among young children including an ongoing collaboration with EHS/HS and expertise in large-scale, multi-ethnic GWAS, create a unique opportunity to carry out this important investigation and advance the knowledge base of genomics of dental caries. The study will improve our understanding of ECC's epidemiology and genomic etiology, key knowledge to reduce the burden of disease in populations of young children, including those underrepresented in research.